2-(substituted-benzyl)-1, 3-propane-dinitriles



United States Patent This invention relates to new organic compounds and, more particularly, is concerned with novel substituted phenylethanes which may be represented by the following general formula:

wherein R is hydrogen, hydroxy, lower alkyl or a lower alkoxy radical, and R and R are hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy or an aralkoxy radical. Suitable lower alkyl and lower 'alkoxy groups contemplated by the present invention are those having up to about 6 carbon atoms. Suitable aralkoxy groups are benzyloxy, phenthoxy, etc. Halogen is exemplified by bromine, chlorine and iodine.

The novel compounds of the present invention are usetul intermediates for the preparation of Z-carboxymethyl and 2-formylmethyl-4-oxo-tetrahydronaphthalenes which form the subject matter of the copending application of Raymond G. Wilkinson and Andrew S. Kende, Serial No. 821,093, filed Tune 18, 1959. The new compounds of this invention are also useful in the synthesis of polyoxygenated cyclic compounds.

The new compounds of this invention may be prepared from the corresponding benzyl bromide according to the following reaction scheme:

R: R1 R2 R1 0 O 0 Et l GHBI diethyl LiAlH4 malonate C O O E t R3 R3 R2 1?] CHzOH R2 R1 /CHg-R CHCH lH-CH KCN onion cnhn.

R2 Elli CHr-CH CH-CH CH -CN wherein R R and R areas hereinbefore defined, and R is chlorine, bromine, iodine, lower alkylsulfonyloxy or an arylsulfonyloxy radical.

The reaction conditions are not especially critical. The reaction of the benzyl bromide with diethyl m'alonate salt is preferably carried out in a refluxing solution of a lower alkanol. The benzyl malonic ester so formed is reduced with lithium aluminum hydride in a conventional manner. The formation of the lbis-sulfonates from the intermediate 1,3 propanediols is likewise conventional.

Alternatively, the bis-halo intermediates may be prepared as shown in the examples which follow. The formation of the dinitrile by reaction with an also conventional.

The invention will be described in greater detail in conjunction with the following specific examples.

Example 1 94.0 grams (0.6 mole) of 2-chloro-5-methoxytoluene [Pena-toner and Condorelli, Gazz. Ohem. Ital. 28, I, 213 (1898)] are added to 600 milliliters of reagent grade carbon tetrachloride, 117.4 grams (0.66 mole) of N-bromosuccinimide and 0.1 gram benzoyl peroxide. The reaction mixture is stirred at reflux temperature and additional 0.1 gram quantities of 'benzoyl peroxide are added after 1% and 18 hours. After 21 hours the volume of solvent is reduced to approximately 250 milliliters and the Succinimide filtered oil. The filtrate is washed with three 200 milliliter portions of water, dried over anhydrous MgSO, and filtered. The solvent is removed under reduced pressure and the residual oil crystallized on standing overnight. Yield of crude 2-ohloro-5-methoxybenzyl bromide, 131.0 grams. The pure compound crystallizes from (20-40) petroleum ether as white needles, melting point 55.5 -57.5 C.

Example 2 131.0 grams (0.55 mole) of Z-chloroS-methoxybenzyl bromide in 300 milliliters of absolute ethanol is added over a 1 hour period to a refluxing solution of diethyl malonate grams, 0.9 mole) and'sodimn methylate (32.4 grams, 0.6 mole) in absolute ethanol. 'I he refluxing is continued for an additional 2% hours and the reaction mixture concentrated to approximately half volume. The sodium bromide is filtered oil and the filtrate acidified by the slow addition of acetic acid. The remainder of the solvent is removed under reduced pressure and the residual oil taken up in ether. The ethereal solution is washed with three 200 milliliter portions of water and dried over anhydrous MgSO The ether and excess diethyl malonate are removed under water pump pressure. Diethyl-Z-chloro-S methoxybenzyl malonate is collected at *168 C./0.4-0.8 mm.; yield: 90.0 grams; n5 1.5030. Overall yield based on 2-chloro-5'-methoxy-toluene is 48% l 1 alkali metal cyanide is Example 3 A solution of 105 grams (0.33 mole) of diethyl-2-' chIoro-S-methoxybenzylmalonate in 360 milliliters of dry ether is added slowly with stirring to 19.5 grams (0.513 mole) of LiAlH, dissolved in 700 milliliters of dry ether. The mixture is stirred and refluxed for 4 /2 hours before decomposing the excess hydride with ethyl acetate. The mixture is acidified with 6 N HCl, washed with water, and allowed to stand over 70 milliliters of 5 N NaOH over the weekend. The other layer is washed with H 0, dried over MgSO and concentrated to an almost colorless oil which turns to a mushy solid on seeding. Distillation at 0.1 mm. gives 64 grams (84%) of a colorless oil at -175 C. with a small forerun a-t 130-160 C. On seeding, the main traction gives white crystals of 2-(2'- chloro-5-methoxy-benzyl)-1,3-propanediol, melting point 41 46 C.

Example 4 To 1.5 grams (5.0 mmole) of 2-(2'-chloro-5-methoxybenzyl)-1,3-propanediol in 10 milliliters of benzene is added 2.20 grams (11.5 mmole) of p toluenesulfonylchloride. The solution was cooled to 0 C. and 1.0 milliliter of pyridine added. This mixture is allowed to stand for 4 days at 5 C. with a considerable amount of pyridine hydrochloride crystallizing out. The solution is filtered and the filtrate is extracted with dilute sodium bicarbonate solution. The benzene layer is concentrated to a gum. This gum can be crystallized from ethanol and water to give white crystals of 2-(2-chloro-5 -methoxybenzyl)-1,3- propanediol-bis-toluenesulfonate.

The majority of the crude gummy 2-(2-chloro-5'-methoxybenzyl) -1,3-propanediol-bis-toluenesulfonate is reacted in 25milliliters of ethanol and 5 milliliters of water with 1.0' gram (20 mmoles) of sodium cyanide. After 16 hours refluxing the mixture is concentrated, extracted with ether, and the ether removed whereby the B-(Z-chloro-S- methoxybenzyl) glutaronitrile is recovered as a residual oil.

Example 5 To a solution of 23.06 grams (0.100 mole) of 2-(2'- chloro-5'-methoxybenzyl) 1,3-propanediol in 100 milliliters of dry benzene is added 24.0 milliliters (0.35 mole) of thionyl chloride. This mixture is allowed to stand at room temperature for 18 hours and is then refluxed for 6 hours. Methanol is added slowly to react with the excess thionyl chloride. The reaction mixture is washed with 2 N NaOH until alkaline, then with water until neutral, dried, and concentrated to yield 2-(2'-chloro 5'-methoxybenzyl)- 1,3-dichloropropaue.

. To this crude oil is added a solution of 45 grams (0.34 mole of NaI in 350 milliliters of acetone. The mixture is refluxed for 5 days with intermittent filtration removing 9.9 grams of NaCl (0.17 mole). The mixture is then concentrated to a mush, water added, and the product extracted with ether. Evaporation of the ether gives an almost black oil from which only small yields of crude product can be obtained by crystallization from ethanol. However, evaporative distillation at 0.1 mm. gives a yellow forerun at about 130 150? 'C., which crystallizes readily from ethanol to give 16.2 grams of whiteneedles M.P. 67-69 C. Additional material is recovered by redistillation of the forerun and the residues yielding 7.2 grams of material melting from 58 to 68 C. Total yield of 2-(2'-chloro-5-methoxybenzyl)-1,3 -diiodopropane, 23.4 grams (52%). Recrystallization from ethanol raises the melting point to 68- 69.5 C.

. Example 6 To 11.90 grams (26.4 mmoles) of 2-(2'-chloro-5'methoxybenzyl)-1,3-diiodopropane dis-solved in 75 milliliters of 95% ethanol is added 4.9 grams (100 mmoles) of C., and a yellow gum from 130 to steam bath under an air jet to give 6.1 gramscf [3-(2- chloro-S-methoxybenzyl) glutaronitrile as a tan 011.

Example 7 2-(2'-chloro-5-methoxybenzyl)-1,3-dibromopropane is (51.2 mmoles) of 2-(2'- 3-propanediol in 25 milliliters (25.2 tribromide and one drop of pyridine and refluxing the mixture for minutes. The

benzene solution is Washed with water, dried over anhydrous magnesium sul-fa-te and concentrated to yield 2-(2'-chloro-5-methoxybenzyl)-1,3-dibromopropane.

13-(2-chloro-5-methoxybenzyl) glutaronitrile from 6.6 grams (1.85 mmoles) of crude Example 8 is prepared 2-(2-chloro-5'- methoxybenzyl)-1,3-dibromopropane in 15 milliliters of absolute ethanol by adding 3.5 grams mmoles) of sodium cyanide in 6 milliliters of water and refluxing the mixture for 18 hours.

The ethanol is removed and the yellow oil which separates is taken up in ether. After washing the ether solution with Water, drying over anhydrous magnesium sulfate and concentrating the yellow oily residue is, in part,

distilled at 0.3 mm. with a colorless oil coming over at -130 C.

This application is a division of our copending application Serial No. 748,589, filed July 15, 1958, now US.

Patent 3,013,069.

sodium cyanide in 10 milliliters of water. This mixture 45 is refluxed 'for 20 hours before concentrating under vacuum. Water is added and the oil which separates is extracted with ether. The ether layer after being dried over anhydrous magnesium sulfate is concentrated on the wherein R pm-CN CHaOH GHz-CN is selected from the group consisting of chic- References Cited in the file of this patent UNITED STATES PATENTS Westfahl Apr. 9, 1957 OTHER REFERENCES Migrdichian, 423, 512 (1957).

Organic Synthesis, vol. 1, pages 11, 225,

(Copy in Sci. Library.) 

1. A COMPOUND OF THE FORMULA: 